PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disease that causes progressive cognitive decline towards dementia. One in nine people over 65 yrs of age in the US has AD and it is the fifth- leading cause of death in this age group. The over 65 population is expected to double by 2050. Delineating factors that predict and prevent cognitive decline related to AD are hugely important but are still poorly understood. This Career Development Award will provide additional training and research opportunities in bioinformatics and neuroinflammation for Dr. Pillai to advance his clinical research skills to address a current knowledge gap in the role for inflammatory factors in AD progression. He is a behavioral neurologist experienced in cognitive neuroscience research with a long-term goal to establish a programmatic body of research using bioinformatics tools to delineate the molecular factors that underpin cognitive decline and disease progression among neurodegenerative diseases. Knowledge of inflammatory factors that drive AD progression will be critical in designing novel therapeutic strategies to prevent cognitive decline. This award will aid him in achieving these goals through a structured training plan that includes formal course work in bioinformatics and statistical techniques, as well as relevant laboratory and clinical research in the immunobiology of AD. He will also receive additional training in grant writing and the design and administration of clinical trials research to facilitate his future focus on bringing bioinformatics insights from large data to bear fruitful impact in the clinic. The research at the foundation of the current application is a clinical translational study that aims to characterize the temporal course of neuroinflammation, blood brain barrier (BBB) integrity and neurodegeneration in AD. Dr.Pillai's preliminary studies in this direction, funded by the Alzheimer Association, suggest that there is a strong relationship between the above three domains, among AD patients at the stage of mild cognitive impairment (MCI). The current award will help Dr.Pillai confirm and extend these insights among healthy, cognitively intact elders who are APOE ?4 risk gene carriers, a significant percentage of whom may be in the preclinical stage of AD. We hypothesize that higher levels of specific baseline cerebrospinal fluid inflammatory markers and BBB break down markers correlate with higher levels of neurodegeneration and impacts cognitive decline over 24 months among these subjects. We will confirm and validate the temporal course of inflammatory protein changes with longitudinal multiplex biomarker and genome wide expression changes over 24 months and against data from other large national data (Alzheimer's Disease Neuroimaging Initiative, Accelerating Medicines Partnership-AD). This research will characterize individual propensities for deleterious inflammatory responses that would be useful for future precision medicine interventions against neuroinflammation in AD to prevent disease progression and cognitive decline